Computational reconstitution of spine calcium transients from individual proteins

We have built a stochastic model in the program MCell that simulates Ca^(2+) transients in spines from the principal molecular components believed to control Ca^(2+) entry and exit. Proteins, with their kinetic models, are located within two segments of dendrites containing 88 intact spines, centered in a fully reconstructed 6 × 6 × 5 μm^3 cube of hippocampal neuropil. Protein components include AMPA- and NMDA-type glutamate receptors, L- and R-type voltage-dependent Ca^(2+) channels, Na^+/Ca^(2+) exchangers, plasma membrane Ca^(2+) ATPases, smooth endoplasmic reticulum Ca^(2+) ATPases, immobile Ca2+ buffers, and calbindin. Kinetic models for each protein were taken from published studies of the isolated proteins in vitro. For simulation of electrical stimuli, the time course of voltage changes in the dendritic spine was generated with the desired stimulus in the program NEURON. Voltage-dependent parameters were then continuously re-adjusted during simulations in MCell to reproduce the effects of the stimulus. Nine parameters of the model were optimized within realistic experimental limits by a process that compared results of simulations to published data. We find that simulations in the optimized model reproduce the timing and amplitude of Ca^(2+) transients measured experimentally in intact neurons. Thus, we demonstrate that the characteristics of individual isolated proteins determined in vitro can accurately reproduce the dynamics of experimentally measured Ca^(2+) transients in spines. The model will provide a test bed for exploring the roles of additional proteins that regulate Ca^(2+) influx into spines and for studying the behavior of protein targets in the spine that are regulated by Ca^(2+) influx

The r-modes in accreting neutron stars with magneto-viscous boundary layers

We explore the dynamics of the r-modes in accreting neutron stars in two ways. First, we explore how dissipation in the magneto-viscous boundary layer (MVBL) at the crust-core interface governs the damping of r-mode perturbations in the fluid interior. Two models are considered: one assuming an ordinary-fluid interior, the other taking the core to consist of superfluid neutrons, type II superconducting protons, and normal electrons. We show, within our approximations, that no solution to the magnetohydrodynamic equations exists in the superfluid model when both the neutron and proton vortices are pinned. However, if just one species of vortex is pinned, we can find solutions. When the neutron vortices are pinned and the proton vortices are unpinned there is much more dissipation than in the ordinary-fluid model, unless the pinning is weak. When the proton vortices are pinned and the neutron vortices are unpinned the dissipation is comparable or slightly less than that for the ordinary-fluid model, even when the pinning is strong. We also find in the superfluid model that relatively weak radial magnetic fields ~ 10^9 G (10^8 K / T)^2 greatly affect the MVBL, though the effects of mutual friction tend to counteract the magnetic effects. Second, we evolve our two models in time, accounting for accretion, and explore how the magnetic field strength, the r-mode saturation amplitude, and the accretion rate affect the cyclic evolution of these stars. If the r-modes control the spin cycles of accreting neutron stars we find that magnetic fields can affect the clustering of the spin frequencies of low mass x-ray binaries (LMXBs) and the fraction of these that are currently emitting gravitational waves.Comment: 19 pages, 8 eps figures, RevTeX; corrected minor typos and added a referenc

CMBPol Mission Concept Study: Probing Inflation with CMB Polarization

We summarize the utility of precise cosmic microwave background (CMB) polarization measurements as probes of the physics of inflation. We focus on the prospects for using CMB measurements to differentiate various inflationary mechanisms. In particular, a detection of primordial B-mode polarization would demonstrate that inflation occurred at a very high energy scale, and that the inflaton traversed a super-Planckian distance in field space. We explain how such a detection or constraint would illuminate aspects of physics at the Planck scale. Moreover, CMB measurements can constrain the scale-dependence and non-Gaussianity of the primordial fluctuations and limit the possibility of a significant isocurvature contribution. Each such limit provides crucial information on the underlying inflationary dynamics. Finally, we quantify these considerations by presenting forecasts for the sensitivities of a future satellite experiment to the inflationary parameters.Comment: 107 pages, 14 figures, 17 tables; Inflation Working Group contribution to the CMBPol Mission Concept Study; v2: typos fixed and references adde

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Jerk limited reference trajectory generation for motion control

M.S.Stephen L. Dickerso

Investigation of neurotransmitter diffusion in three- dimensional reconstructions of hippocampal neuropil

A comprehensive explanation of neuronal function requires that we understand how cellular structure seen in the brain shapes neuronal activity. For instance hippocampal CA1 synapses do not confine glutamate to the cleft following vesicular release of neurotransmitter but instead allow glutamate to diffuse out into the extracellular space, a phenomenon called 'spillover'. Combining accurate representations of the cellular structure with Monte Carlo simulations of glutamate diffusion in the extracellular space following vesicular release allows us to investigate where glutamate goes after it is released into a synapse. Here we describe a process for the creation of three-dimensional reconstructions of neuropil from two-dimensional EM images. We employed the method to generate three- dimensional reconstructions of the extracellular space from electron microscopy images and subsequent corrections informed by in vivo morphological parameters reported in the literature. Quantitative measurements of the reconstruction are consistent with reports that fixed tissue is shrunken compared to in vivo state with an especially large reduction in extracellular volume fraction. The reconstruction most likely to reflect in vivo conditions has an extracellular volume fraction of 22%, median extracellular width of 40 nm, and glutamate diffusion constant in the extracellular space of 4.5e-6 cm²/sec. As a prelude to simulations of spillover in the reconstruction we constructed a simplified three- dimensional model of hippocampal neuropil and used the model to perform Monte Carlo simulations of spillover following high-frequency burst release of neurotransmitter. The mean radial diffusion distance of a quantum of transmitter was independent of quantal size over the range tested. More than 90% of the diffusing neurotransmitter stays within 2 $$mu$$m of the release site after synaptic vesicular release. Glutamate transporters suppress NMDAR spillover activation almost entirely, while AMPAR spillover activation is nonexistent with or without transporters. Glutamate transporters are not saturated with vesicle size of 3000 glutamate even after 100Hz burst in either model. Our results suggest that glutamate spillover is insignificant in neuropil models with canonical geometry and can be ignored. However, it remains to be seen whether spillover is relevant in the heterogeneous milieu of real neural tissue

Computational reconstitution of spine calcium transients from individual proteins.

We have built a stochastic model in the program MCell that simulates Ca(2+) transients in spines from the principal molecular components believed to control Ca(2+) entry and exit. Proteins, with their kinetic models, are located within two segments of dendrites containing 88 intact spines, centered in a fully reconstructed 6 × 6 × 5 μm(3) cube of hippocampal neuropil. Protein components include AMPA- and NMDA-type glutamate receptors, L- and R-type voltage-dependent Ca(2+) channels, Na(+)/Ca(2+) exchangers, plasma membrane Ca(2+) ATPases, smooth endoplasmic reticulum Ca(2+) ATPases, immobile Ca(2+) buffers, and calbindin. Kinetic models for each protein were taken from published studies of the isolated proteins in vitro. For simulation of electrical stimuli, the time course of voltage changes in the dendritic spine was generated with the desired stimulus in the program NEURON. Voltage-dependent parameters were then continuously re-adjusted during simulations in MCell to reproduce the effects of the stimulus. Nine parameters of the model were optimized within realistic experimental limits by a process that compared results of simulations to published data. We find that simulations in the optimized model reproduce the timing and amplitude of Ca(2+) transients measured experimentally in intact neurons. Thus, we demonstrate that the characteristics of individual isolated proteins determined in vitro can accurately reproduce the dynamics of experimentally measured Ca(2+) transients in spines. The model will provide a test bed for exploring the roles of additional proteins that regulate Ca(2+) influx into spines and for studying the behavior of protein targets in the spine that are regulated by Ca(2+) influx